3-enol esters of 6-halo-16alpha-hydroxy cortical hormones



'3-ENOL ESTE-RS F s-rrArlo-rsa-rirnnoxY CORTICAL HORMONES Howard J.Ringold, Carl Dje'r'as'si, and Albert Bowers, all of Mexico City,Mexico, assignors toSyntex S.A., Mexico City, Mexico, a corporation ofMexico No Drawing. Filed June 16, 1959, Ser. No. 820,589

Claims priority, application Mexico June 17, 1958 14 Claims. (Cl.260-23955) The present invention relates to novelcyclopentanophenanthrene derivatives.

More particularly, it relates to the novel B-enol-ethers of the 6-haloand 6a,9u-dihalo analogs of steroidal 16ozhydroxy cortical hormones, andeven more specifically, to a 3-alkoigy--pregnadiene-16a,17a,21-triol-20-one oxygenated at C-11 with ap-hydroxyl or keto group, fluorinated 0r chlorinated at 0-6 or at C-6and C-9, optionally esterified at 0-21 or at C-16 and 0-21, and whichmay also be under the" form of their 16a,17aacetals or cyclic ketals.

The new compounds object of the present invention are hormones havinganti-inflammatory, :glycogenic, thymolytic, anti-androgenic,anti-estrogenic and catabolic activity.

The novel hormones just referred to are illustrated by the followingformulas:

In the above formulas X represents fluorine or chlorine. X representshydrogen, fluorine or chlorine. Y represents mula I with a triester oforthoformic acid, preferably I with a triester formed with loweraliphatic alcohols of 2-5 carbon atoms; we usually carried out thereaction in mixture with dioxane, in the presence of a p-toluenesulfonicacid and at room temperature, although the solvent, the catalyst and theother reaction conditions can I tates Patent 0 2,985,652 Patented May23, 1961 Ice be varied. Thus we produced the desired enol-etl'iers,represented by Formula II.

orno R" I II X=F or Cl; X'=H, E or Cl; Y'=fi-OH, OCOF or 0:; R'=H; R andR"=H or acyl; R, R may also mean the residue of an acetal or ketal,represented by the following Formula (III):

CHQR" A and B represent a hydrogen atom or any'hydrdcarbon residue;these starting acetals and keta1s" h'ave been recently described byRingold, Z'der'ic', Djer'assi and Bowers in a copending United Statesapplication Serial No. 819,545, filed June 11, 1959. A and B may alsoform part of a ring or of a cyclic hydrocarbon, such as cyclohexa'ne forexample when the*16a,17a-dihydroxy, steroid is allowed to react withcyclohexane. The other starting materials have also been described inother United States applications (of. Ringold and. Bowers, applicationSerial No. 762,232, filed September 22, 1958; Ringold, Mancera' andKincl, application Serial No. 753,626, filed August 7, 1958). Theesterification of an llfi -hydroxy group with trifiuoroacetic acid ishereinafter described.

By the aforementioned enolization of a 60:,90t-dih8l0- A-pregnene-11fl,l6a,17a,2l-tetrol 3,20 dione, we ob-- tained therespective 3-alkoxy-6,9a-dihalo-A-pregnadiene-l119,16a,17a,21-tetrol-20one; by enolization of a 61xhalo-A-pregnene-l6a,l7u,21-t1iol-3,11,20=trione We obtained a 3-alkoxy6-halo-A -pregnadiene-16a,l7u,21- triol-lLZQ-dion; a 6a,9u-di'haloA-pregnei1e-l6a,17a,2ltriol-3,ll,20-trione gave the respective3-alkoxy-6,9a'-dihalo-A pregnadiene-l6a,17oz,2l-triol 1l,20-diorre; weconverted a 16a,l7ot-cyclic ketal or acetal or such A -cornpounds intothe 16oz,17a-cyclic *ketal or acetal of their 3- enol ethers'; using theA -compounds under the form of their 2-1-monoesters (described for thenon ketaliz'ed compounds having a fluorine atom at 0-6, and for all ofthe ketals or acetals) We obtained the respective 21- esters of FormulaII; by enolization of the 16,2l-diesters of the non-ketalized compoundsmentionedabove, we produced the 16,21-diesters of their 3-enol-ethers.

In thecompounds of Formula I having only a halogen atom at C-6 andhaving an llp-hydroxyl group, we temporarily protected this hydroxylgroup by esteri- ,fication with an acid which forms esters easy tosaponify;

.methanol containing a little pyridine. .obtained6,9a-difluoro-3aethoxy-n -pregnadiene-115,16a,

. 3 preferably we esterified the llfl-hydroxyl group by reaction withtrifluoroacetic anhydride in mixture with dioxane; we converted a16,21-diesters of a 6a-halo-A pregnene-l1B,l6u,17a,21-tetrol-3,20-dioneinto its ll-trifluoroacetate-l6,21-diacylate, then into the respectivel1- trifiuoroacetate-l6,2l-diacylate of the corresponding 6-halo-3-alkoxy-A -pregnadiene-1 1B,l6oc,l7oc,2l-te'tr01 20- bne andfinally hydrolyzed the esterified groups of the latter; by theesterification of the llfi-hydroxyl group of a 21-ester of a16u,17a-cyclic ketal or acetal of a 6a-halo-M-pregnene-llfi,l6a,1Za,2l-tetrol3,20-dione followed by enolization weobtained the" respective II-jtrifluOro-acetate- 2l-acylate of thecorresponding 16d,17oc-cyclic' near or acetal of the 3-alkoxy-6-halo-A-pregnadiene-113,16, l7u,21-tetro1-20-one; the ester groups of thelatter were then hydrolyzed. I The hydrolysis of the ester groupsof allof the aforementioned compounds, as wellas'of the compounds of FormulaII, when obtained as the estersprwas carried but preferably by treatmentwith 'a dilute methanolic solution of potassium hydroxide or sodiummethoxide, at low temperature and under ari'atrnosphere of nitrogen.l'he primary and secondary hydroxyl groups of the compounds of FormulaII were esterified by reaction with the anhydride of any hydrocarboncarboxylic acid of up to 12 carbon atoms, in pyridine solution; theanhydride wasderived from an acid saturated or unsaturated, of

straight, branched, or cyclic chain, substituted or not with methoxy,halogen or other groups, or having a chain combining thesecharacteristics. Thus, among other 2l-monoesters and 16,2l-diesters,respectively, we produced the acetates, propionates, butyrates,hemisuccinates, caproates, nanthates, benzoates, trimethylacetates,acetoxyacetates, phenoxyacetates, cyclopentylpropionates,phenylpropiohates and B-chloropropionates.

Our method can also be applied to compounds having a bromine atom at -6,at C-9 or at both of these positions, We only describe the reactionsstarting from compounds having the halogen atom at position 60s, but the-6fl-halo-isomers can be reacted with the same result.

The following specific examples serve to illustrate the presentinvention but are not intended to limit the same:

Example I A solution of g. of 6a,9a-difluoro-A -pregnene- 11p,l6a,17x,21-tetrol-3,20-dione in 100 cc. of dioxane was mixed with 5 cc. ofethyl orthoformateand 200 mg. of p-to'luenesulfonic acid and the mixturewas stirred for 40 -minutes at room temperature; 6.5 cc. of pyridine'wasthen added and the mixture was slowly diluted with water,

under stirring,'to.precipitate the reaction product which was extractedwith ethyl acetate. The extract was washed 'withiwater dried overanhydrous sodium sulfate and "the ethyl acetate was evaporated; theresidue crystallized from methanol containing a few drops of pyridine,to

'21-tetrol-20-one.

A mixture'of 2.2 gIof the above compound, cc. of pyridine and 1.1 molarequivalents of acetic anhydride was with water, dried and recrystallizedfrom aqueous There was thus -l7a,21 tetrol-20-one 21-acetate.

Example II In another, experiment, 2 g. of ,6,9a-difluoro-3-ethoxy- A-pregnadiene-l1B,16a,l7m,21-tetrol-20-one, intermediate in the previousexample, was acetylated in pyridine 4 producing 6,91!difluoro-3-ethoxy-A -pregnadienc-1113, 16u,l7a,2 1-tetrol-20-one16,2l-diacetate.

Example 111 In the method of Example I, there was substituted the ethylorthoformate by the tripropyl ester of orthoformic acid, thus afiording6,9ot-difiuoro-3-propoxy-A -pregnadiene-l1B,16a,l7a,21-tetrol-20-one,which was then converted into its 21-monoacetate, in accordance withsuch example, or into its 16,21-diacetate, in accordance with ExampleII.

Example IV In the method of Example I, there was substituted 6a, 9adifluoro-M-pregnened113,l6a,17u,2l-tetrol-3,20-dione by its 21-acetate.There was directly obtained 6,9oc-difluoro 3 ethoxy-A-pregnadiene-l,1;8,16a,l7u,2l-tetroh 20-one'21-acetate, identical withthe final compound of Example I.

Example V By substituting in the method of Example I60:,902-dlfluoro-M-pregnene-l15,16a,17a,2l-tetrol-3,20-dione by its16,2l-diacetate, there was directly obtained 6,9m-difluoro- 3 ethoxy-A-pregnadiene-l113,16a,17a,21-tetrol-20-one l6,21-diacetate, identicalwith the compound obtained in accordance with Example II.

Example VI Example VII By substituting in the methods of Examples I andII the acetic anhydride by the anhydride of another hydrocarboncarboxylic acid of up to 12 carbon atoms, or starting in the method ofExamples 4'and 5 with other esters different from the acetate, therewere obtained the enolized compounds under the form of the correspondingesters;

solution with an excess of acetic anhydride, overnight at a 'roomtemperature; the 'acetylation product was isolated by following themethod described in such example, thus '11B,16a,17a,21-tetr0l-20-one andalso the furthermore, there were obtained other enol-ethers by usinganother triester of orthoformic acid; for example,

there were prepared the 21-propionates and 16,21-dipropionates of6,9a-difluoro-3-butoxy-A -pregnadienecorrespondingcyclopentylpropionates and benzoates.

Example VIII In accordance with the method of Example I, 5 g. of thel6e,l7a-(acetaldehyde)-cyclic ketal of 6a-chloro-9a-'fluoro-l6a-hydroxy-hydrocortisone ZI-acetate, namely 6mmethoxide wasstirred at 0 under an atmosphere of nitrogen for 1 hour; the mixturewas, poured into ice cold saturated sodium chloride solution andthe'reaction product was extracted with methylene chloride, washed withwater, dried over anhydrous sodium sulfate and the solvent-wasevaporated. Recrystallization of the residue from acetone-hexanefurnished 1 the free 6-chloro-9afluoro 3ethoxy-l6e,17a-methylmethylenedioxy-A pregnadiene-l15,2l-diol-20-one.

By treatment of the above compound with an excess ofcyclopentylpropionic' acid anhydride in pyridine solution, 'at roomtemperature for a long period of time, there was obtainedits21-cyclopentylpropionate.

Example IX In accordance with the previous methods, there were formedthe 3-enol-ethers of all of the other ca-nato (fluoro and chloro) and6a,9a-dihalo (fluoro and chloro) analogs of 16a-hydroxy-cortisone, oftheir 21-monoe'sters A mixture of 2 g. of the acetonide of 6u-chloro-Apregnene-l1e,16a,17a,2l-tetrol-3,20-dione 21-acetate, 12 cc. ofanhydrous dioxane and 4.6 g. of trifluoroacetic anhydride was stirred atroom temperature for 18 hours and then poured into ice water; theacylation product was extracted several times with methylene chlorideand the combined extract was washed with water to neutral, dried overanhydrous sodium sulfate and evaporated to dryness. The residue wastriturated with ether, thus giving the 1l-trifluoroacetate-Zl-acetate ofthe acetonide of 6u-chloro-A -pregene-11/3,16a,17a,21-tetrol-3,20-dione,which was used for the subsequent enolization without furtherpurification. In another experiment the tetroldione was obtained in pureform by chromatography on neutral alumina.

A solution of 2 g. of the above crude compound in 40 cc. of dioxane wastreated with 2 cc. of ethyl orthoformate and 80 mg. ofp-toluensesulfonic acid for 40 mintues; 2.6 cc. of pyridine was thenadded and the reaction product was isolated by the method described inExample I. There was thus obtained the 16a,17aacetonide of the1l-trifiuoroacetate-Zl-acetate of 6-chloro-3- ethoxy-A-pregnadiene-l1,8,16a,17u,21-tetro1-20-one.

A mixture of 1 g. of the above compound and 10 cc. of absolute methanolwas treated with a solution of 100 mg. of sodium in 5 cc. of methanoland kept for 1 hour at a temperature around C. and under an atmosphereof nitrogen. After pouring into 100 cc. of aqueous saturated sodiumchloride solution the compound was extracted with methylene chloride andthe extract was washed with water, dried over anhydrous sodium sulfateand evaporated to dryness. Crystallization of the residue fromacetone-hexane yielded the free l6a,l7a-acetonide of 6 chloro 3ethoxy-A-pregnadiene-11,8,16u,l7a,2ltetrol-20-one.

By treatment of 500 mg. of the above compound with 10 cc. of pyridineand 1 cc. of cyclopentylpropionic acid anhydride at room temperature for24 hours, there was obtained the corresponding 21-cyclopentylpropionate.The product was isolated by pouring into water, extracting withmethylene chloride, evaporating to dryness the washed extract andrecrystallizing the residue from acetone-hexane.

In the same way there was formed the same derivatives of other ketals oracetals including those of formaldehyde, paraldehyde, benzaldehyde,acetophenone, diethylketone, chloroacetone and furfural.

Example XI Before the enolization, there was protected in the samemanner the 11 fl-hydroxyl group of all of the other starting compoundshaving an l1/3-hydroxyl group and only one halogen atom at C-6a; from a16,21-diacy1ate of a 6m halo APICgI16116-1lfl,16a,17a,21-t6tI'Ol-3,20-dl0fl6 there was prepared its1l-trifluoroacetate-16,21-diacylate; from a 21-ester of a l6a,l7a-cyclicketal or acetal of a 602 halo Aprenegne-llfl,l6a,17a,2l-tetrol-3,20-dione there was prepared its11-trifluoroacetate-2l-acylate; these compounds were then subjected tothe reaction with the triester of orthoformic acid; the ester groups ofthe enolized compounds were subsequently hydrolyzed; the primary andsecondary hydroxyl groups of the free compounds were re-esterified byreaction with the anhydride of any carboxylic acid of up 12 carbonatoms, including acetic, cyclopentlypropionic acid benzoic.

For example, there was formed the ll-trifluoroacetate- 16,21-diacetateof 6tx-fluoro-A -pregnened1p,16a,17a,2ltetrol-3,20-dione; the latter wasconverted into the 11- trifluoroacetate-16,21-diacetate of6-fluoro-3-ethoxy-A pregnadiene-l1,8,16a,17a,21-tetrol-20 one byreaction with ethyl orthoformate; the ester groups were hydrolized byreaction with sodium methoxide in methanol solution to produce the freehydroxyl groups; the free 6-fluoro- 3- ethoxy-A-pregnadiene-115,16a,17a,21-tetro1-20-one was treated with an excess ofpropionic anhydride in pyridine solution, to produce the16,21-dipropionate of such compound.

We claim: 1. A compound of the following formula:

omo R" Y -o R c g Ell/OJ wherein X is selected from the group consistingof fluorine and chlorine; X is selected from the group consisting ofhydrogen, fluorine, and chlorine, R" is selected from the groupconsisting of hydrogen and a hydrocarbon carboxylic acyl group of up to12 carbons when R is hydrogen, and R and R are both selected from thegroup consisting of hydrogen and a hydrocarbon carboxylic acyl group ofup to 12 carbon atoms, R is lower alkyl and Y is selected from the groupconsisting of OH =0 and {H 2. A compound of the following formula:

CHQO R wherein X is selected from the group consisting of fluorine andchlorine, X is selected from the group consisting of hydrogen, fluorineand chlorine, R" is selected from the group consisting of hydrogen and ahydrocarbon carboxylic acid acyl group of up to 12 carbon atoms, Y isselected from the group consisting of OH =0 and H 7. 6,90: difluoro 3propoxy-u -pregnadien-l1B,

16a,17a,21-tetrol-20-one ZI-acetate.

1. A COMPOUND OF THE FOLLOWING FORMULA:
 2. A COMPOUND OF THE FOLLOWINGFORMULA: